Process for producing imidazole derivatives

ABSTRACT

The present invention provides a process for producing a compound of the formula (III): ##STR1## wherein R 1  and R 3  are independently hydrogen or an organic group; R 2  is an organic group; and R 4  is an optionally substituted aryl. by reacting the compound of formula (I): ##STR2## wherein R 1 , R 2 , and R 3  are as defined above, with the compound of formula (II): 
     
         R.sup.4 --S--Hal                                           (II) 
    
     wherein R 4  is as defined above and Hal is halogen, in the presence of base.

TECHNICAL FIELD

The present invention relates to a process for producing imidazolederivatives.

BACKGROUND ART

Various imidazole derivatives have been researched to apply them tomedicines, and the present inventors found that the imidazolederivatives having an arylthio group at 5-position were efficient as anantiviral agent or an anti-HIV agent.

It is known, as a process for producing imidazole derivatives having asubstituted thio group, that halogenated imidazole derivatives arereacted with mercaptane/NaH/DMF after formation of an imidazole ring(HETEROCYCLES, Vol 33, No 1, 21-26, (1992)). It is also known thatimidazole derivatives are reacted with disulfide in the presence of abase after halogenation of --CH of the imidazole ring (J. Chem. PerkinTrans. I 1139-1145 (1989) and WO 96/10019). These methods are, however,inappropriate to the reaction on an industrial scale because theyrequire halogenation of --CH of the imidazole ring and a strong basesuch as NaH or the like. As mentioned above, a process for producingimidazole derivatives having a substituted thio group, which isappropriate to convenient, economical, large-scaled production, has notbeen known heretofore.

DISCLOSURE OF INVENTION

The present inventors have intensively studied to develop convenient,economical, large-scaled production of substituted thio imidazolederivatives such as 5-arylthio imidazole derivatives, and succeeded inthe reaction of imidazole derivatives of the following formula (I) withthiohalide of the formula (II) in the presence of a base to giveimidazole derivatives having a substituted thio group of the formula(III). Thus, the present invention has been accomplished.

Accordingly, the present invention provides a process for producing acompound of the formula (III): ##STR3## wherein R¹ and R³ areindependently hydrogen or an organic group; R² is an organic group; andR⁴ is an optionally substituted aryl, which comprises reacting acompound of the formula (I): ##STR4## wherein R¹, R², and R³ are asdefined above, with a compound of the formula (II):

    R.sup.4 --S--Hal                                           (II)

wherein R⁴ is as defined above and Hal is halogen, in the presence of abase.

BEST MODE FOR CARRYING OUT THE INVENTION

A preferable embodiment of the present invention includes the processwherein the organic groups in the formula (I) are an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted aryl, an optionally substituted thioaryl, an optionallysubstituted heteroaryl, an optionally substituted heteroarylalkyl, anoptionally substituted aralkyl, an optionally substituted acyl, anoptionally substituted carbamoyl, an optionally substitutedalkoxycarbonyl, --CH═NOH, --CH═NNH₂, or --A--X wherein A is --CH₂ OCH₂-- or --CH₂ O-- and X is an optionally substituted aryl or --COR⁵wherein R⁵ is an optionally substituted alkyl, an optionally substitutedalkoxy, an optionally substituted aryl, or an optionally substitutedamino.

The more preferable embodiment of the present invention is (l) theprocess wherein R¹ is hydrogen or an optionally substitutedheteroarylalkyl; R² is --A--X wherein A is --CH₂ OCH₂ -- or --CH₂ O--and X is an optionally substituted aryl or --COR⁵ wherein R⁵ is anoptionally substituted alkyl, an optionally substituted alkoxy, anoptionally substituted aryl, or an optionally substituted amino; and R³is an optionally substituted alkyl. In particular, the process forproducing the compound wherein R¹ is optionally substitutedpyridylmethyl (esp. pyridin-4-ylmethyl) is preferred. Especially, theprocess for the compound wherein R² is benzyloxymethyl, acetyloxymethyl,benzoyloxymethyl, methoxycarbonyloxymethyl, and carbamoyloxymethyl ispreferred.

A preferable compound of the formula (II) is (2)3,5-dichlorobenzenesulfenyl chloride.

A preferable base is (3) triethylamine or N-methylmorphorine.

The terms used in the present specification are defined below.

The term "organic group" refers to an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted aryl, anoptionally substituted arylthio, an optionally substituted heteroaryl,an optionally substituted heteroarylalkyl, an optionally substitutedaralkyl, an optionally substituted acyl, an optionally substitutedcarbamoyl, an optionally substituted alkoxycarbonyl, --CH═NOH,--CH═NNH₂, --A--X wherein A is --CH₂ OCH₂ -- or --CH₂ O-- and X is anoptionally substituted aryl or --COR⁵ wherein R⁵ is an optionallysubstituted alkyl, an optionally substituted alkoxy, an optionallysubstituted aryl, or an optionally substituted amino, and the like.

The term "alkyl" means a C1-C20 straight or branched chain alkyl, forexample, methyl, ethyl, n-propyl, i-prolyl, n-butyl, i-butyl, t-butyl,n-pentyl, i-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, andthe like. A C1-C6 lower alkyl is preferred.

The "alkyl" portion of the term "alkoxy" means an alkyl as definedabove, for example, methoxy, ethoxy, propoxy, t-butoxy, and the like.

The term "alkenyl" means a C2-C20 straight or branched alkenyl, forexample, vinyl, allyl, propenyl, butenyl, pentenyl, hexyenyl, heptenyl,and the like. A C2-C7 lower alkenyl is preferred.

The term "aryl" means phenyl or naphthyl. Examples of an optionallysubstituted aryl include, for example, 3,5-dichlorophenyl,2,4-difluorophenyl, 3,5-difluorophenyl, 3,5-dimethylphenyl,3,5-dimethoxyphenyl, 2,4,6-trimethylphenyl, 3,5-di-t-butylphenyl,4-methoxyphenyl, 4-benzylphenyl, 4-hydroxyphenyl, 3,5-dinitrophenyl,3-nitrophenyl, 3,5-diaminophenyl, 3-aminophenyl, and the like.

The term "heteroaryl" means a 5-7 membered heterocyclic group containingat least one hetero atom (N, O, or S), for example, pyridyl (e.g.,4-pyridyl), pyrimidinyl (e.g., 2-pyrimidinyl), pyridazinyl (e.g.,3-pyridazinyl), pyrazinyl (e.g., 2-pyrazinyl), thienyl (e.g.,2-thienyl), quinolyl (e.g., 3-quinolyl), imidazolyl (e.g.,2-imidazolyl), oxazolyl (e.g., 2-oxazolyl), thiazolyl (e.g.,5-thiazolyl), and the like. Pyridlyl is preferred.

The term "heteroarylalkyl" means the above defined alkyl substitutedwith the above defined heteroaryl, for example, pyridylmethyl (e.g.,4-pyridylmethyl), pyridylethyl (e.g., 1- or 2-(2-pyridyl)ethyl),pyridylpropyl (e.g., 3-(2-pyridyl)propyl), thienylmethyl (e.g.,2-thienylmethyl), quinolylmethyl (e.g., 3-quinolylmethyl),imidazolylmethyl (e.g., 2-imidazolylmethyl), and the like.

The term "aralkyl" means the above defined alkyl substituted with theabove defined aryl, for example, benzyl, phenethyl (e.g., 1-phenethyl),naphthylmethyl, naphthylethyl (e.g., 2-naphthylethyl), and the like.

The term "acyl" means an aliphatic or aromatic acyl, for example,acetyl, propionyl, pivaloyl, benzoyl, and the like.

The "optionally substituted carbamoyl" may optionally be mono- ordi-substituted with a substituent as described below, for example,N-methylcarbamoyl, N,N-dimethylcarbamoyl, and the like.

The term "alkoxycarbonyl" refers to , for example, methoxycarbonyl,etboxycarbonyl, and the like.

The term "halogen" means fluoro, chloro, bromo, and iodo. Chloro orbromo is preferred.

The "optionally substituted amino" may optionally be mono- ordi-substituted with a substituent as described below, for examplemethylamino, dimethylamino, and the like.

When each group as described above is substituted, the substituentrefers to, for example, an alkyl (e.g., methyl and ethyl), a halogen(fluoro, chloro, bromo, and jodo), an acyl (e.g., acetyl and benzoyl),an alkenyl (e.g., allyl), a cycloalkyl (e.g., cyclopropyl), an aralkyl(e.g., benzyl), an optionally substituted amino (e.g., methylamino anddimethylamino), hydroxy, oxo, an alkoxy (e.g., methoxy and ethoxy),cyano, carboxy, an alkoxycarbonyl (e.g., methoxycarbonyl), nitro, anacyloxy (e.g., acetyloxy). an optionally substituted carbamoyl (e.g.,N-methylcarbamoyl), an optionally substituted carbamoyloxy (e.g.,N-ethylcarbamoyloxy), and the like. One or more substituent(s) may be atany substitutable position(s). When the substituent interferes thereaction, a protective group may be introduced before the reaction, andthen removed at any suitable step after the reaction.

The compound of the formula (I), the starting materials of the presentinvention, includes known ones and may be produced according to themethod described in the International Patent Publication WO 96/10019 andthe Japanese Patent Unexamined Publication 116242/1994. The compound ofthe formula (I) to be used in the present invention is, for example,2-benzyloxymethyl-4-isopropylimidazole,2-benzyloxymethyl-4-isopropyl-{1-(4-pyridylmethyl)}imidazole,2-acetyloxymethyl-4-isopropyl-{1-(4-pyridylmethyl)}-imidazole,2-benzoyloxymethyl-4-isopropyl-{1-(4-pyridlylmethyl)}-imidazole,2-methoxycarbonyloxymethyl-4-isopropyl-{1-(4-pyridylmethyl)}-imidazole,2-carbamoyloxymethyl-4-isopropyl-{1-(4-pyrid(ylmethyl)}-imidazole, andthe like.

The compound (II) is commercially available or produced by reacting thecorresponding disulfide (R⁴ --S)₂ wherein R⁴ is an optionallysubstituted aryl, which is produced in accordance with known methods,with chlorine gas. The disulfide is, for example,bis(3,5-dichlorophenyl)disulfide, bis(4-chlorophenyl)disulfide,bis(2-chlorophenyl)disulfide, bis(4-nitrophenyl)disulfide,bis(2-nitrophenyl)disulfide, bis(2,4-dinitrophenyl)disulfide,bis(4-methoxyphenyl)disulfide, bis(4-methylphenyl)disulfide,bis(2,4,6-trimethylphenyl)disulfide, diphenyldisulfide, and the like.The amount of chlorine gas to be used in the preparation of the compound(II) is 1-3 mole equivalents to the disulfide (R⁴ --S)₂. The reactionmay be carried out by introducing chlorine gas at 30-60° C. into anorganic solvent (e.g., tetrachloromethane, chloroform, dichloromethane,toluene) in which a suitable amount of disulfide is dissolved.

The compound (II) is, for example, 3,5-dichlorobenzenesulfenyl chloride,4-chlorobenzenesulfenyl chloride, 2-chlorobenzenesulfenyl chloride,4-nitrobenzenesulfenyl chloride, 2-nitrobenzenesulfenyl chloride,2,4-dinitrobenzenesulfenyl chloride, 4-methoxybenzenesulfenyl chloride,4-methylbenzenesulfenyl chloride, 2,4,6-trimethylbenzenesulfenylchloride, and the like.

A base to be used for the reaction of the compound (I) with the compound(II) is, for example, triethylamine, N-methylmorpholine, pyridine,N,N-dimethylaniline, N,N-diisopropyl-N-ethylamine, butyl lithium,diazabicycloundecene, and the like. A solvent is, for example,acetonitrile, toluene, dichloromethane, chloroform, dimethylformamide,nitromethane, benzene, tetrahydrofuran, and the like.

In the reaction of the present invention, the amount of a base is 0.1-3mole equivalents, preferably 1-2 mole equivalents to the compound (I)and the amount of the compound (II) is 1-3 mole equivalents, preferably1-2 mole equivalents to the compound (I). The reaction temperature canbe -30-60° C., preferably 0-10° C. The reaction time can be 0.5-24hours, preferably 0.5-3 hours. The compound (1) can be generally addedto the compound (II) with stirring and vice versa. A base is eithermixed with compound (I) in advance, or added at the end.

The following examples are provided to further illustrate the presentinvention and are not to be construed as limiting the scope thereof.

The meanings of the following abbreviations in the examples are shownbelow.

    ______________________________________                                        Me              methyl                                                          Ph phenyl                                                                     Bn benzyl                                                                     TEA triethylamine                                                             DMF N,N-dimethylformamide                                                   ______________________________________                                    

REFERENCE EXAMPLE 1 3,5-Dichlorobenzenesulfenyl chloride (2)

Bis(3,5-dichlorophenyl)disulfide 15.0 g (42.1 mmol) was dissolved intetrachloromethane (60 ml). The solution was added dropwise to asolution of chloride gas 9.0 g (126.9 mmol) in tetrachloromethane (50ml) at -10° C. The mixture was kept standing 20 min at the sametemperature, to which the dried nitrogen gas was bubbled for removingexcessive chlorine. The resulting mixture was concentrated under reducedpressure to yield the objective (2) 18.6 g (quantitative) as a red oil.

¹ H-NMR (CDCl₃ -TMS) δ ppm: 7.32 (t, J=1.8 Hz, 1H), 7.43 (d, J=1.8 Hz,2H)

REFERENCE EXAMPLE 2 3,5-Dichlorobenzenesulfenyl chloride (2)

Bis(3,5-dichlorophenyl)disulfide 30.0 g (84.2 mmol) was dissolved intoluene (90 ml). To the solution was introduced chlorine gas 11.9 g(167.8 mmol) under ice-cooling for 1 hour. The dried nitrogen gas wasbubbled into the mixture at the same temperature for removing excessivechlorine to yield the toluene solution of the objective (2). Yield99.7%.

EXAMPLE 12-Benzyloxymethyl-5-(3,5-dichloropbenylthio)-4-isopropyl-1H-imiidazole(3) ##STR5##

2-Benzyloxymethyl-4-isopropyl-1H-imidazole (1) 550 mg (2.4 mmol),described as a reference example 1 in WO 96/10019, was dissolved in themixture of triethylamine 360 mg (3.6 mmol) and acetonitrile 4 ml. To thesolution was added 3,5-dichlorobenzenesulfenyl chloride (2) 930 mg (4.4mmol) at, room temperature. The mixture was stirred for 30 minutes atroom temperature and water 15 ml and toluene 15 ml were added thereto.The toluene layer was separated, washed with water 10 ml twice, andconcentrated under reduced pressure. The obtained yellow oil wascrystallized with dilsopropyl ether 10 ml, filtered, and dried to yieldthe objective (3) 800 mg as a pale yellow crystal. Yield 82%.

¹ H-NMR (CDCl₃ -TMS) δ ppm: 1.22 (d, J=7.2Hz, 6H), 3.64 (sept, 1H), 4.62(s, 2H), 4.67 (s, 2H), 6.92 (bs, 2H), 7.07 (bs, 1H), 7.36 (s, 5H), 9.20(b, 1H).

EXAMPLE 22-Benzyloxmethl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-pyrilin-4-yl)methyl-1H-imidazole(5) ##STR6##

2-Benzyloxymethyl-4-isopropyl-1-(pyridin-4-yl)-1H-imidazole (4) 10.0 g(31.1 mmol) was dissolved in toluene (50 ml). The solution was addeddropwise to a toluene solution 24.7 g of 3,5-dichlorobenzenesulfenylchloride (2) 8.0 g (37.05 mmol) under ice-cooling for 30 minutes. To themixture was added dropwise triethylamine 3,5 g (34.6 mmol) underice-cooling for 1 hour, and the mixture was stirred at, the sametemperature for 1.5 hour. To the mixture was added water 25 ml, andtoluene layer was ejarated. The toluene layer was washed with water 25ml, and each aqueous layer was extracted with toluene 10 ml. The toluenelayer was collected, concentrated un(der reduced pressure, crystallizedwith diusopropyl ether 50 ml, filtered, and dried to the objective (5)12.6 g as a pale yellow crystal. Yield 81.3%.

¹ H-NMR (CDCl₃) δ ppm: 1.30 (d, J=7.2 Hz, 6H), 3.08-3.22 (m, 1H), 4.52(s, 2H, 4.62 (s, 2H) 5.16 (s, 2H), 6.65 (d, J=1.8 Hz, 2H), 6.79 (d,J=6.0 Hz, 2H), 7.03 (t, J=1.8 Hz, 1H), 7.18-7.36 (m, 5H), 8.38 (d, J=6.0Hz, 2H).

REFERENCE EXAMPLE 3 2-Acetyloxymethyl-4-isopropyl-1-(pyridin-4-yl)methyl-1H-imidazole (7a) ##STR7##

The compound (4) 20.0 g (62.2 mmol) was suspended in 35% aqueoushydrochloric acid 100 ml. The solution was heated at 85° C. and stirredfor 1 hour. The reaction mixture was cooled down to room temperature,and water 100 ml and toluene 44 ml were added thereto. The aqueous layerwas separated, neutralized with aqueous 30% sodium hydroxide, andstirred after addition of ethyl acetate 30 ml. The obtained slurry wasfiltered, washed with cold water, and dried to yield2-hydroxymethyl-4-isopropyl-1-(pyridin-4-yl)-1H-imidazole (6) 11.7 g.Yield 81.4%.

¹ H-NMR (CDCl₃) δ ppm: 1.16 (d, J=7.0 Hz, 6H), 2.68-2.89 (m, 1H), 4.59(s, 2H), 5.23(s, 2H), 6.51 (s, 1H), 7.03 (d, J=6.0 Hz, 2H), 8.55 (d,J=6.0 Hz, 2H).

To a solution of the above-obtained hydroxy compound (6) 3.49 g (15mmol), dichloromethane 35 ml, and triethylamine 1.83 g (18 mmol) wasadded dropwise acetylchloride 1.32 g (17 mmol) under ice-cooling and themixture was stirred for 1 hour under ice-cooling. Water was addedthereto, and the dichloromethane layer was separated, concentrated, andpurified by column chromatography on silica gel (elution ethyl acetate:methanol=10:1) to yield the objective (7a) 3.34 g. Yield 81.1%.

¹ H-NMR (CDCl₃) δ ppm: 1.26 (d, J=7.0 Hz, 6H), 1.85 (s, 3H), 2.88-3.05(m, 1H), 5.11 (s, 2H), 5.15 (s, 2H), 6.64 (s, 1H), 6.95 (d, J=6.0 Hz,2H), 8.59 ((d, J=6.0 Hz, 2H.

In accordance with the same method described above, the above-obtainedhydroxy compound (6) 1.16 g (5 mmol), dichloromethane 12 ml,triethylamine 0.86 g (8.5 mmol), and benzoylchloride 1.16 g (8.3 mmol)were reacted to yield the objective (7b) 1.65 g. Yield 93.2%. (elution:ethyl acetate)

¹ H-NMR (CDCl₃) δ ppm: 1.34 (d, J=7.0 Hz, 6H), 2.90-3.10 (m, 1H), 5.29(s, 2H), 5.45 (s, 2H), 6.74 (s, 1H), 6.99 (d, J=6.0 Hz, 2H), 7.30-7.90(m, 5H), 8.55 (d, J=6.0 Hz, 2H).

In accordance with the same method described above, the above-obtainedhydroxy compound (6) 1.16 g (5 mmol), dichloromethane 12 ml,triethylamine 0.76 g (7.5 mmol). and methyl chloroformate 0.70 g (7.4mmol) were reacted to yield the objective (7c), methoxycarbonyloxyderivative, 0.40 g. Yield 27.6%.

¹ H-NMR (CDCl₃) δ ppm: 1.25 (d, J=7.0 Hz, 6H), 2.80-3.00 (m, 1H), 3.70(s, 3H), 5.17 (s, 2H), 5.18 (s, 2H), 6.64 (s, 1H), 6.97 (d, J=6.0 Hz,2H), 8.59 (d, J=6.0 Hz, 2H).

EXAMPLE 32-Acetyloxymethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-(pyridin-4-yl)methyl-1H-imidazole(8) ##STR8##

To a toluene solution 1.88 g of the compound (2) 0.97 g (4.5 mmol) wasadded dropwise an acetonitrile solution 4 ml of the compound (7a) 0.87 g(3.2 mmol) under ice-cooling for 30 minutes. The solution oftriethylamine 0.46 g (4.5 mmol) and acetonitrile 0.5 ml was addeddropwise thereto for 15 minutes, and the mixture was stirred underice-cooling for 2 hours. The reaction mixture was concentrated underreduced pressure and extracted with ethyl acetate. The extract waswashed with water, concentrated under reduced pressure, and purified bycolumn chromatography on silica gel (elution ethyl acetate) to yield theobjective (8) 1.17 g as a crystal. Yield 82%. Mp 133-135° C.

¹ H-NMR (CDCl₃ -TMS) δ ppm: 1.31 (d, J=6.0 Hz, 6H), 1.85 (s, 3H),3.18-3.30 (m, 1H), 5.18 (s, 2H), 5.19 (s, 2H) 6.69 (d, J=2.0 Hz, 2H),6.78 (d, J=6.0 Hz, 2H), 7.05 (d, J=2.0 Hz, 1H), 8.45 (d, J=6.0 Hz, 2H).

REFERENCE EXAMPLE 42-Hydroxymethyl-5-(3,5-dichlorophenyithio)-4-isopropyl-1-(pyridin-4-yl)methyl-1H-imidazole(9) ##STR9##

To an ethanol suspension 3.5 ml of the compound (8) 0.35 g (0.77 mmol)obtained in example 3 was added 1N aqueous sodium hydroxide 0.82 ml. Thereaction mixture was stirred for 30 minutes, concentrated under reducedpressure, and extracted with ethyl acetate. The extract was washed withwater and concentrated under reduced pressure to yield the objective (9)0.31 g. Yield 96.9%.

REFERENCE EXAMPLE 52-Carbamoyloxymethyl-4-isopropyl-1-(pyridin-4-yl)methyl1H-imiidazole(10) ##STR10##

The hydroxy compound (6) 15.0 g (64.9 mmol) was suspended inacetonitrile 150 ml. To the solution was added dropwise anhydroushydrochloric acid 5.2 g (142.5 mmol) in ethyl acetate 42 ml at roomtemperature. The mixture was cooled down to 0° C. under nitrogenatmosphere, and chlorosulfonyl isocyanate 22.0 g (155.4 mmol) was addedthereto under cooling for 45 minutes. The reaction mixture was stirredat the same temperature for 1 hour, and water 13.5 ml and 35% aqueoushydrochloric acid 13.5 ml were added thereto. The mixture was stirred at45° C. for 1 hour, cooled down to room temperature, and neutralized by20% aqueous sodium carbonate. The mixture was kept stationary andseparated. The organic layer was washed with water, and the aqueouslayer was extracted with ethyl acetate. The organic layer was collected,concentrated, and dried. To the residue was added diusopropyl ether 80ml, and the solution was stirred for 1 hour at room temperature. Theobtained slurry was filtered. washed with dilsopropyl ether, and driedto yield the objective (10) 14.8 g (yield 83.2%).

¹ H-NMR (CDCl₃ -TMS) δ ppm: 1.25 (d, J=7.0 Hz, 6H), 2.80-3.00 (m, 1H),4.95 (bs, 2H), 5.10 (s, 2H), 5.20 (s, 2H), 6.63 (s, 1H), 6.97 (d, J=5.2Hz, 2H), 8.57 (d, J=5.0 Hz, 2H).

EXAMPLE 42-Carbamoyloxymethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-(pyridin-4-yl)methyl-1H-imidazole(11) ##STR11##

The compound (10) 250 mg (0.91 mmol) was dissolved inN,N-dimethylformamide 4 ml. The solution was cooled down to -30° C.under nitrogen atmosphere. To the solution were added alternately fourtimes a toluene solution 150 mg of the compound (2) 77 mg (0.36 mmol)and a toluene solution 150 mg of triethylamine 36 mg (0.36 mg), andadditionally added a toluene solution 150 mg of the compound (2) 77 mg(0.36 mmol). The reaction mixture was stirred at -30° C. for 30 minutes,and ethyl acetate and aqueous sodium hydrogen carbonate were addedthereto. The objective (11) was extracted with ethyl acetate. Dilutedaqueous hydrochloric acid was added thereto, and the objective wasre-dissolved in aqueous layer. The aqueous solution was neutralized byaqueous sodium hydrogen carbonate and extracted with ethyl acetate. Theextract was dried over anhydrous sodium sulfate and concentrated underreduced pressure to prepare oily residue. The oily residue was dissolvedin methanol 0.9 ml, and water 0.7 ml was added for 1-2 minutes at, roomtemperature thereto to prepare the precipitate. The suspension wasstirred for 30 minutes at room temperature, additionally stirred for 30minutes under ice-cooling, filtered, washed with 50% aqueous methanol,and dried to yield the objective (11) 250 mg as a white crystal. Yield61%. mp 88° C. (dec)

¹ H-NMR (CDCl₃ -TMS) δ ppm: 1.32 (d, J=6.9Hz, 6H), 3.17 (sept, 1H), 4.53(b, 2H), 5.21 (s, 2H), 5.27 (s, 2H), 6.69 (d, J=1.6 Hz, 2H), 6.82 (d,J=5.2 Hz, 2H), 7.06 (t, J=1.6 Hz, 1H), 8.46 (b, 2H). Element analysis(C₂₀ H₂₀ Cl₂ N₄ O₂ S.0.5H₂ O); Calcd. (%): C, 52.16: H, 4.61: N, 12.17:S, 6.96: Cl, 15.42; Found.(%): C, 52.45: H, 4.72: N, 11.73: S, 7.08: Cl,14.81; 2HCl salt of the compound (11): mp 214-222° C. (dec)

REFERENCE EXAMPLE 6 (I) 2,2-Dichloro-3-methylbutylaldehyde (13)##STR12##

To the mixture of isovalelaldehyde (12) 192 g (2.23 mol) andN,N-dimethylformamide 230 ml was introduced chlorine 316 g (4.46 mol)under 60° C. The mixture was cooled down, mixed with water 384 ml, andseparated. The organic layer was washed with aqueous sodium hydrogencarbonate 350 g, and each aqueous layer was extracted with toluene 115ml. The organic layer was collected to yield the toluene solution 440 gof the objective (13). (Yield 75%).

¹ H-NMR (CDCl₃ -TMS) δ ppm: 1.15 (d, J=6.6 Hz, 6H), 2.56 (sept, J=6.6Hz, 1H). 9.24 (s, 1H).

(II) 1,4-Dibenzyloxy-2-butene (15) ##STR13##

To 48% aqueous sodium hydroxide 127.8 g was added tetra-n-butylammoniumbromide 3.3 g (10 mmol), and the mixture was heated to 60° C. To themixture was added 2-butene-1,4-diol (14) 30.0 g (340 mmol), to which wasadded dropwise benzyl chloride 94.8 g (743 mmol) at 80±15° C. Themixture was stirred at the same temperature for 2 hours. The reactionmixture was cooled down, and separated after addition of water 90 ml. Tothe organic layer was add sulfuric acidic brine. The solution wasneutralized by aqueous sodium hydrogen carbonate, separated, mixed withethyl acetate, and concentrated under reduced pressure to yield the oilresidue 104.5 g (quantitative) of the objective (15).

¹ H-NMR (CDCl₃ -TMS) δ ppm: 4.05 (d, J=3.8 Hz, 2H), 4.48 (s, 2H), 5.78(m, 2H), 7.31 (m, 10H).

Benzyloxyacetoaldehyde (16) ##STR14##

1,4-Dibenzyloxy-2-butene (15) 104.5 g (340 mmol) obtained above wasdissolved in methanol 1458 ml. The solution was cooled down to -60° C.under nitrogen atmosphere. Ozone was introduced thereto at -60° C. untilthe starting material was disappeared, and then the excess amount ofozone gas was removed by bubbling nitrogen gas. To the solution wasadded dropwise an ethyl acetate solution 550 ml of triphenylphosphine107.2 g (409 mmol) at -60° C. to reduce the reaction intermediate. Thereaction mixture was warmed to room temperature, and concentrated underreduced pressure to yield the oily mixture 321.6 g (quantitative) ofphosphorous compound and the objective (16).

(III) 2-Benzyloxymethyl-4-isopropyl-1H-imidazole (17) ##STR15##

The oil residue 268 g (approximately 0.57 mol) obtained in (II) of thebenzyloxy acetaldehyde (16) and the extract 183 g (0.70 mol) obtained in(I) of 2,2-dichloro-3-methylbutylaldehyde (13) were mixed withacetonitrile 276 ml. 25% aqueous ammonia was added thereto. The mixturewas stirred at 45° C. for 8 hours, extracted with toluene 213 ml andseparated to yield the extract, 725 g (yield 70%) of the objective (17).The compound (17) can be crystallized by hexane.

¹ H-NMR (CDCl₃ -TMS) δ ppm: 1.23 (d, J=6.8 Hz, 6H), 2.88 (sept, J=6.8Hz, 1H), 4.51 (s, 2H), 4.58 (s, 2H), 6.65 (d, J=1.0 Hz, 1H), 7.1-7.4 (m,5H).

(IV) 4-Chloromethylpyridine hydrochloride (19) ##STR16##

4-Hydroxymethylpyridine (18) 54.4 g (0.50 mol) was dissolved inacetonitrile 202 ml. The solution was added dropwise to the mixture ofthionyl chloride 65.3 g (0.55 mol) and acetonitrile 109 ml under 50° C.The mixture was stirred at the same temperature for 1 hour, then cooledto room temperature to yield the slurry (quantitative) of the objective(19).

¹ H-NMR (DMSO-TMS) δ ppm: 5.09 (s, 2H), 8.09 (d, J=6.6 Hz, 2H), 8.94 (d,J=6.6 Hz, 2H),

(V) 2-Benzyloxymethyl-4-isopropyl-1-(pyridin-4-yl)methyl-1H-imidazole2nitrate (20) ##STR17##

The extract 725 g (approximately 0.40 mol) obtained in (III) of2-benzyloxymethyl-4-isopropyl-1H-imidazole (17) was neutralized byaqueous sulfuric acid, mixed with the slurry (approximately 0.50 mol)obtained in (IV) of 4-chloromethylpyridine hydrochloride (19) and water,and then alkalified by aqueous sodium hydroxide. The mixture wasseparated, the aqueous layer was extracted with toluene 65 ml, and theorganic layer was collected. The organic layer was concentrated to 830ml, mixed with sodium hydroxide 62.6 g, and stirred at 40° C. for 5hours. The reaction mixture was mixed with water 226 ml and separated.The aqueous layer was extracted with toluene 65 ml, and the organiclayer was collected. The organic layer was mixed with 20% aqueoussulfuric acid 348 g and the aqueous layer was separated. The organiclayer was extracted with water 65 ml, and the aqueous layer wascollected. The aqueous layer was mixed with 20% aqueous sodium hydroxide282 g and extracted with ethyl acetate 130 ml. The organic layer waswashed with brine, and each aqueous layer was extracted with ethylacetate 65 ml. The organic layer was collected, concentrated underreduced pressure, and dried. The residue was mixed with ethyl acetate523 ml and methanol 131 ml, crystallized by concentrated sulfuric acid82.9 g (0.89 mol), filtered, and dried to yield the objective (20) 161.3g as a pale yellow crystal. Yield 90%. mp 155° C. (dec).

The free compound of the objective (20) can be crystallized bydiisopropyl ether.

¹ H-NMR (CD₃ OD-TMS) δ ppm: 1.34 (d, J=7.0 Hz, 6H), 3.08 (sept, J=7.0Hz, 1H), 4.86 (s, 2H), 4.89 (s, 2H), 5.78 (s, 2H), 7.16 (m, 2H), 7.28(m, 2H), 7.49 (d, J=1.0 Hz, 1H), 7.74 (d, J=6.8 Hz, 2H), 8.67 (d, J=6.8Hz, 2H).

2-Benzyloxymethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-pyridin-4-yl)methyl-1H-imidazole(5) ##STR18##

2-Benzyloxymethyl-4-isopropyl-1-pyridin-4-yl)-1H-imidazole 2 nitrate(20) 13.9 g (31 mmol) was suspended in toluene 50 ml and water 12 ml.The solution was neutralized by 30% aqueous sodium hydroxide. Thetoluene layer was washed with water 40 ml, concentrated, and dried. Theresidue was dissolved in toluene 50 ml. The solution was added dropwiseto toluene solution 24.7 g of 3,5-dichlorobenzenesulfenylchloride (2)7.9 g (37 mmol). To the mixture was added dropwise triethylamine 3.5 g(34 mmol) under ice-cooling for 1 hour. The mixture was stirred at thesame temperature for 2.5 hours, and mixed with water 25 ml. The toluenelayer was separated and washed with water 25 ml, and the aqueous layerwas re-extracted with toluene 10 ml. The toluene layer was collected andconcentrated under reduced pressure. The residue was crystallized bydilsopropyl ether, filtered, and dried to yield the objective (5) 13.0 gas a pale yellow crystal. Yield 84%.

¹ H-NMR (CDCl₃) δ ppm: 1.30 (d, J=7.2 Hz, 6H), 3.08-3.22 (m, 1H), 4.52(s, 2H), 4.62 (s, 2H) 5.16 (s, 2H ), 6.65 (d, J=1.8 Hz, 2H), 6.79 (d,J=6.0 Hz, 2H ), 7.03 (t, J=1.8 Hz, 1H), 7.18-7.36 (m, 5H), 8.38 (d,J=6.0 Hz, 2H ).

2-Hydroxymethyl-5-(3,5-dichlororhenylthio)-4-isopropyl-1-(pyridin-4-yl)methyl-1H-imidazole(9) ##STR19##

To the compound (5) was added aqueous concentrated hydrochloric acid 50ml. The mixture was heated at 90° C. for 2 hours and then cooled down.To the mixture were added water 50 ml and toluene 20 ml. The aqueouslayer was separated and neutralized by 30% aqueous sodium hydroxide. Thecompound (9) was extracted with ethyl acetate 50 ml, and the ethylacetate layer was washed with water 30 ml. Each aqueous layer wasextracted with ethyl acetate 20 ml. The ethyl acetate layer wascollected and concentrated under reduced pressure to yield oily residue.To the oily residue was slowly added diisopropyl ether 50 ml. Theobtained slurry was stirred at room temperature for 30 minutes,filtered, washed with diusopropyl ether 30 ml, and dried to yield thecompound (9) 10.4 g as a white crystal. Yield from the compound (20):82%

2-Carbamoyloxymethyl-5-(3,5-dichloroihenylthio)-4-isopropyl-1-(pyridin-4-yl)methyl-1H-imidazole(11) ##STR20##

The hydroxy compound (9) 2.00 g (4.9 mmol) was suspended in ethylacetate 20 ml, and the solution was cooled down to -30° C. undernitrogen atmosphere. To the solution was added dropwise chlorosulfonylisocyanate 1.66 g (11.4 mmol) under nitrogen atmosphere at -30° C. for30 minutes, and the mixture was stirred at the same temperature for 1hour. To the mixture was added dropwise water 2 ml, and the mixture waswarmed up to 0° C. To the mixture were added 35% aqueous hydrochloricacid 2 ml and methanol 4 ml, and the solution was stirred at 40° C. for1 hour. The mixture was cooled down to room temperature and neutralizedby 20% aqueous sodium carbonate. The organic layer was separated, washedwith water, concentrated, and dried. To the residue was added methanol 6ml and after that water 6 ml at room temperature. The obtained slurrywas filtered, washed with 50% aqueous methanol 6 ml, and dried to yieldthe compound (11) 2.06 g (yield 93.2%).

¹ H-NMR (CDCl₃ -TMS) δ ppm: 1.32 (d, J=6.9 Hz, 6H), 3.17 (sept, 1H),4.53 (b, 2H ), 5.21 (s, 2H), 5.27 (s, 2H ), 6.69 (d, J=1.6 Hz, 2H), 6.82(d, J=5.2 Hz, 2H) 7.06 (t, J=1.6 Hz, 1H), 8.46 (b, 2H). Element analysis(C₂₀ H₂₀ Cl₂ N₄ O₂ S.0.5H₂ O ); Calcd. (%): C, 52.16: H, 4.61: N, 12.17:S, 6.96: Cl, 15.42; Found. (%): C, 52.45: H, 4.72: N, 11.73: S, 7.08:Cl, 14.81; 2HCl salt of the compound (11): mp 214-222° C. (dec)

EXAMPLES 5-6

Compounds described blow were produced in the same manner as describedabove to establish reaction conditions.

                  TABLE 1                                                         ______________________________________                                          #STR21##                                                                       -                                                                              #STR22##                                                                     -  Example                                                                   No. R.sup.1 R.sup.2                                                         ______________________________________                                        1            H          CH.sub.2 OBn                                            " " "                                                                         2 CH.sub.2 -4-pyridyl "                                                       3 " CH.sub.2 OCOMe                                                            4 " CH.sub.2 OCONH.sub.2                                                      5 " CH.sub.2 OCOPh                                                            6 " CH.sub.2 OCOOMe                                                         ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                               Com-                  Reaction                                                                              Reaction                                   Example pound 2 TEA  temperature time Yield                                   No. mol eq. mol eq. Solvent (° C.) (hour) (%)                        ______________________________________                                        1      1.8     1.5     CH.sub.3 CN                                                                         r.t.    0.5    82                                  " 1.8 1.5 toluene 50-55 2.5 82                                                2 1.2 1.1 toluene 0-5 2.0 81                                                  3 1.4 1.4 CH.sub.3 CN 0-5 2.0 82                                              4 2.0 1.6 DMF 30 0.5 61                                                       5 1.4 1.2 CH.sub.3 CN 0-5 2.0 85                                              6 1.4 1.2 CH.sub.3 CN 0-5 1.0 83                                            ______________________________________                                    

INDUSTRIAL APPLICABILITY

The present invention provides a process for producing imidazolederivatives (III) useful as an antiviral agent and an anti-HIV agent,which is applicable to convenient, economical production on a largescale.

We claim:
 1. A process for producing a compound of the formula (III):##STR23## wherein R¹ and R³ are independently hydrogen or an organicgroup; R² is an organic group; and R⁴ is an optionally substituted aryl,which comprises reacting the compound of the formula (I): ##STR24##wherein R¹, R², and R³ are as defined above, with a compound of theformula (II):

    R.sup.4 --S--Hal                                           (II)

wherein R⁴ is as defined above and Hal is halogen, in the presence of abase.
 2. The process as claimed in claim 1 wherein the organic group isan optionally substituted alkyl, an optionally substituted alkenyl, anoptionally substituted aryl, an optionally substituted arylthio, anoptionally substituted heteroaryl, an optionally substitutedheteroarylalkyl, an optionally substituted aralkyl, an optionallysubstituted acyl, an optionally substituted carbamoyl, an optionallysubstituted alkoxycarbonyl. --CH═NOH, --CH═NNH₂, or --A--X wherein A is--CH₂ O CH₂ -- or --CH₂ O-- and X is an optionally substituted aryl or--COR⁵ wherein R⁵ is an optionally substituted alkyl, an optionallysubstituted alkoxy, an optionally substituted aryl, or an optionallysubstituted amino.
 3. The process as claimed in claim 1 wherein R¹ ishydrogen or an optionally substituted heteroarylalkyl; R² is --A--Xwherein A is --CH₂ O CH₂ -- or --CH₂ O-- and X is an optionallysubstituted aryl or --COR⁵ wherein R⁵ is an optionally substitutedalkyl, an optionally substituted alkoxy, an optionally substituted aryl,or an optionally substituted amino; and R³ is an optionally substitutedalkyl.
 4. The process as claimed in claim 1 wherein R¹ is an optionallysubstituted pyridylmethyl.
 5. The process as claimed in claim 1 whereina compound of the formula (II) is 3,5-dichlorobenzenesulfenyl chloride.6. The process as claimed in claim 1 wherein said base is triethylamineor N-methylmorpholine.